General Discussion

Santavuori disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic diseases known as the neuronal ceroid lipofuscinoses (NCL). These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Santavuori disease is considered the infantile form of the neuronal ceroid lipofuscinoses. The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body. This may result in the progressive deterioration (atrophy) of certain areas of the brain in addition to neurological impairment and other characteristic symptoms and physical findings.

In most cases, infants with Santavuori disease appear to develop normally until approximately nine to 19 months of age. They may then begin to exhibit a delay in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). In addition, affected infants begin to lose previously acquired physical and mental abilities (developmental regression). Affected infants may then experience a variety of symptoms including episodes of uncontrolled electrical disturbances in the brain (seizures), impaired ability to coordinate voluntary movements (cerebellar ataxia), abnormally diminished muscle tone (hypotonia), and repeated, brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic seizures). Affected infants also experience progressive visual impairment due to deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the nerve-rich membranes lining the eyes (retina) to the brain (optic atrophy). Neurological impairment continues to progress and may be characterized by an inability to move voluntarily (immobility); sudden involuntary muscle spasms (spasticity); and lack of response to stimuli in the environment. Life-threatening complications may develop by the end of the first decade. Santavuori disease is inherited as an autosomal recessive trait.

Signs & Symptoms

In most cases, infants with Santavuori disease appear to develop normally until approximately nine to 19 months of age. They may then begin to show indifference to stimuli that would normally be of interest (apathy), may appear unusually sluggish both mentally and physically, and may begin to exhibit abnormal delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). In addition, affected infants may experience episodes of uncontrolled electrical disturbances in the brain (seizures). Affected children typically lose previously acquired physical and mental abilities (developmental regression) such as the ability to speak. In addition, in children with Santavuori disease, the head and brain cease growing after approximately the first year of life. As a result, affected children develop microcephaly by the age of approximately two years. Microcephaly is a condition that indicates a smaller head circumference than would be expected for an infant’s age and sex.

In addition, as affected children experience developmental regression, several neuromuscular abnormalities also begin to appear. Affected children demonstrate an impaired ability to coordinate voluntary movements (cerebellar ataxia). (The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement.) In addition, they may demonstrate certain repetitive involuntary movements such as unusual “knitting” hand movements. Because of the lack of coordination of the legs, affected children may be unable to walk or stand, although some may have previously acquired such skills earlier in development. In addition, at this stage of the disorder, many children may have generalized muscular weakness and diminished muscle tone (hypotonia) usually accompanied by abnormally exaggerated tendon responses. By the second year of life, most affected children experience repeated, brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic seizures).

Early in the course of the disease, infants and children with Santavuori disease also exhibit various abnormalities of the nerve-rich membrane lining the eyes (retina). Such abnormalities may include narrowing of the retinal blood vessels, abnormal yellowish-gray or brown coloring (pigmentation) of the normal depression on the retina that plays an essential role in color vision (macula), and/or, in some cases, progressive degeneration of the colored layer of the retina (pigmentary retinal degeneration). In addition, shortly after the onset of symptoms, affected children may begin to experience rapidly progressive visual impairment due to deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the retinas to the brain (optic atrophy). In most cases, affected children experience complete vision loss by the end of the second year of life.

Neurological deterioration continues to progress in affected children and, by approximately the third year of life, may be characterized by loss of electrical activity of certain areas of the brain (electrocortical activity); an inability to move voluntarily (immobility); sudden involuntary muscle spasms (spasticity) with exaggerated reflexes; uncontrolled, rigid extension and rotation of the arms, legs, fingers, and toes due to abnormalities of the brain (decerebrate rigidity); and/or no response to stimuli in the environment. Life-threatening complications may develop by the end of the first decade.

Causes

Santavuori disease is transmitted as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

Investigators have determined that Santavuori disease results from abnormal changes (mutations) of a gene that encodes the enzyme known as palmitoyl-protein thioesterase (PPT). According to researchers, deficiency of the PPT enzyme appears to be the primary defect responsible for the symptoms and findings associated with the disease.

The gene that encodes that PPT enzyme is located on the short arm (p) of chromosome 1 (1p32). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered.

In individuals with Santavuori disease, abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain and other tissues of the body result in progressive deterioration (atrophy) of certain areas of the brain (e.g., cerebrum and cerebellum), neurologic impairment, and other symptoms and physical findings characteristic of the disorder. As mentioned above, Santavuori disease appears to be a lysosomal storage disorder that results from deficiency of the lysosomal enzyme palmitoyl-protein thioesterase (PPT). Lysosomes are the primary digestive units within cells. Enzymes within lysosomes break down or “digest” nutrients, such as fats and carbohydrates. In the lysosomal storage disorders, deficiency or improper functioning of particular lysosomal enzymes may lead to an abnormal accumulation of certain complex compounds consisting of fatty materials and/or carbohydrates within the cells of particular tissues of the body.

Affected Populations

According to the medical literature, Santavuori disease, which appears to affect males and females in equal numbers, has been reported worldwide. However, the disorder most commonly occurs in individuals of Northern European Scandinavian ancestry, particularly individuals of Finnish heritage. According to reports in the literature, one in approximately 13,000 to 20,000 infants in Finland has the disorder. Santavuori disease, along with the other forms of neuronal ceroid lipofuscinoses, is estimated to occur in approximately one in 25,000 live births iIn the United States.

Related Disorders

Symptoms of the following disorders may be similar to those of Santavuori disease. Comparisons may be useful for a differential diagnosis:

Jansky-Bielschowsky disease is the late infantile form of neuronal ceroid lipofuscinosis (NCF). The onset of symptoms associated with the disorder typically begins between the ages of two to four years of age. Until that time, children with the disorder appear to develop normally or may exhibit slight delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). Between two to four years of age, they may then begin to experience seizure episodes characterized by sudden breaks in action or thought, twitching of certain facial muscles, and/or spasms of the neck and/or arms (petit mal seizures) and/or episodes characterized by loss of consciousness occurring in association with muscle contractions (grand-mal seizures). Affected children also begin to demonstrate repeated, brief, shock-like muscle spasms of the arms, legs, or entire body (myoclonic seizures); impaired ability to coordinate voluntary movement (ataxia); abnormally diminished muscle tone (hypotonia) with unusually exaggerated reflexes; gradual intellectual deterioration; and/or, in some cases, visual failure due to retinal degeneration. In addition, a variant of Jansky-Bielschowsky disease has been identified in individuals of Finnish descent. In this variant form, symptoms tend to appear later, at approximately five to seven years of age, and tend to progress more slowly than in the classic form of the disorder. Jansky-Bielschowsky disease and its variant form (neuronal ceroid lipofuscinosis variant late infantile type) are inherited as autosomal recessive traits.

There are four major disorder types belonging to the inherited neurometabolic diseases known as the neuronal ceroid lipofuscinoses (NCL). In addition to Santavuori disease (infantile type) and Jansky-Bielschowsky disease (late infantile type), described above, these disorders also include Batten disease (juvenile type), which is also called Spielmeyer-Vogt disease, and Kufs disease (adult type). Some researchers use the term Batten disease to encompass all forms of NCL; other still use it to denote only the juvenile form. Although the juvenile and adult forms of these disorders are characterized by symptoms similar to those associated with the infantile and late infantile forms, the onset of symptoms occurs later in life. Such symptoms typically include gradual intellectual deterioration, seizure episodes, progressive movement (motor) impairment, and, in the case of Batten disease, progressive visual impairment. In individuals with Batten disease, symptoms begin to occur at approximately five to 13 years of age. In those with Kufs disease, symptoms associated with the disorder may not appear until the third or fourth decade of life. Batten disease and Kufs disease are thought to be inherited as autosomal recessive genetic traits. (For more information on these disorders, choose “Batten” and “Kufs” as your search terms in the Rare Disease Database.)

Alpers disease, a rare condition that typically becomes apparent during early childhood, is characterized by progressive mental deterioration and motor impairment, repeated seizures that are unresponsive to anticonvulsant drug therapy (intractable epilepsy), and, in some cases, impaired liver function. Many of the symptoms associated with the disorder appear to be due to degeneration of nerve cells of the brain. Researchers believe that Alpers disease, rather than being a distinct disorder, is a condition that may be due to a number of different underlying causes. (For more information on this condition, choose “Alpers” as your search term in the Rare Disease Database.)

Rett syndrome is a rare progressive neurological disorder that occurs only in females. In most cases, affected children appear to develop normally until approximately six to 18 months of age, at which time their psychomotor development may seem to halt and they may begin to lose previously acquired physical and mental abilities (developmental regression). In addition, in children with Rett syndrome, the head and brain cease growing during early childhood. As a result, although the head circumference is normal at birth, affected children appear to have an abnormally small head (microcephaly) by the age of one year. As the disorder progresses, affected children lose the ability to perform purposeful movements with their hands and begin to demonstrate certain repetitive involuntary (stereotypical) hand movements (e.g., rubbing, “handwashing,” etc.). Additional symptoms may include abnormally rapid or deep breathing (hyperventilation), seizure episodes, progressive loss of additional motor abilities, and/or other abnormalities. Many symptoms associated with the disorder appear to be due to progressive degeneration of certain areas of the brain (encephalopathy). The exact cause of Rett syndrome is unknown. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)

Diagnosis

Because the disease gene responsible for Santavuori disease has been identified, genetic testing may aid in the accurate diagnosis of the disorder and assist in diagnosis before birth (prenatally) as well as carrier determination. However, it is possible that such testing may only be available through research laboratories with a special interest in this disease.

In some cases, prenatal diagnosis may be performed through the use of chorionic villus sampling (CVS). During CVS, tissue samples are removed from a portion of the placenta and specialized enzyme tests (assays) and DNA studies may be performed. In cases of Santavuori Disease, such evaluations (e.g., mutation analysis and fluorometric PPT enzyme analysis) may reveal abnormal changes (mutations) of the PPT gene and deficient PPT enzyme activity. According to researchers, prenatal testing may also be feasible through the use of amniocentesis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed. Studies have demonstrated that specialized enzyme assays (fluorometric PPT enzyme analysis) conducted on amniotic fluid cells may also reveal deficient activity of the PPT enzyme. Such prenatal screening procedures may be considered for families with a history of Santavuori disease.

In many cases, Santavuori disease may be diagnosed or confirmed during the first years of life based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests. According to the medical literature, the childhood NCLs such as Santavuori disease should be considered in infants or children who begin to experience developmental regression and seizure episodes in association with progressive visual impairment.

As with prenatal diagnosis, postnatal diagnostic techniques may include DNA studies (e.g., mutation analysis) as well as specific enzyme assays (e.g., fluorometric PPT enzyme analysis) that may reveal deficient PPT enzyme activity in certain cells. For example, in individuals with the disorder, deficient activity of the PPT enzyme may be demonstrated in certain skin cells (fibroblasts), white blood cells (leukocytes), the fluid portion of the blood (plasma), and the cerebrospinal fluid.

In addition, diagnostic procedures may include the microscopic examination (i.e., electron microscopy) and study of the chemical components (histochemical examination) of samples of tissue (biopsy), usually from the skin (i.e., sweat glands) or from the transparent membrane covering the whites of the eyes (conjunctiva). In some cases, tissue from the nerves outside the brain and spinal cord (peripheral nerves) and/or from the brain may be biopsed and studied. In cases of Santavuori disease, study of such tissue samples reveals abnormal accumulations of fatty, granular deposits (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) in membrane-bound cavities within the body (cytoplasm) of cells (inclusion bodies). Similar granular deposits may also be present in other tissues and cells of the body (e.g., certain white blood cells [lymphocytes], lymph nodes, pancreas).

Additional specialized tests may be conducted to detect certain abnormalities typically associated with Santavuori disease. Microscopic examination of tissue from certain portions of the brain's cerebrum and cerebellum (e.g., cortices, central gray structures) may reveal near absence of nerve cells (neurons), an abnormally increased number of specialized cells that serve to eliminate waste products of nerve tissue (histiocyte-microgliocytes), and the presence of certain cells that tend to accumulate due to destruction of nearby neurons (astrocytes). In addition, microscopic examination of retinal tissue may reveal destruction of nerve cells that respond to light stimuli (photoreceptor cells).

Advanced imaging techniques may also reveal the presence and/or extent of specific abnormalities associated with Santavuori disease. For example, magnetic resonance imaging (MRI) and computer-assisted tomography (CT scanning) of the brain may reveal abnormal smallness of the brain (microencephaly) and progressive, generalized deterioration (diffuse atrophy) of the cerebrum and the cerebellum. During MRI, a magnetic field and radio waves are used to create cross-sectional images of the brain. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure.

Early in the course of the disease, electroencephalography (EEG), which records the brain's electrical impulses, may reveal brain wave patterns that are characteristic of certain types of seizure activity. Later during the disease's course, EEG testing may reveal rapidly progressive diminishing of electrical activity in certain areas of the brain (electrocortical activity). In addition, in children with Santavuori disease, electroretinography (ERG), a special instrument that measures the retina's electrical response to light stimulation, may reveal lack of response when the eye is stimulated by light (visually evoked potential [VEP]), confirming progressive retinal pigmentary degeneration and/or optic nerve abnormalities (e.g., optic atrophy).

Standard Therapies

Treatment

The treatment of Santavuori disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat neurological disorders (neurologists), eye specialists (ophthalmologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Specific therapies for Santavuori disease are symptomatic and supportive. In some cases, treatment with anticonvulsant drugs may help prevent, reduce, or control various types of seizures associated with Santavuori disease. Genetic counseling will be of benefit for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

Affected individuals are being recruited for a study of the use of a drug called Cystagon as a therapy for infantile neuronal ceroid lipofuscinosis (Santavuori disease). This study is sponsored by the National Institute for Child Health and Human Development of the National Institutes of Health. Only patients between six months and three years of age will be admitted to the study. For details, contact the NIH Patient Recruitment Office (see above) or visit the www.clinicaltrials.gov web site.

Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., seizures, visual impairment, etc.].)

NORD's Rare Disease Database provides brief introductions for patients and their families to more than 1,200 rare diseases. This is not a comprehensive database since there are nearly 7,000 diseases considered rare in the U.S. We add new topics as we are able to do so, with the help of rare disease medical experts.

If you are seeking information about a rare disease that is not in this database, we would suggest contacting the Genetic and Rare Diseases Information Center (GARD) at the National Institutes of Health. NIH has the most complete database of rare diseases in the U.S.

Representatives of patient organizations whose medical advisors are interested in assisting NORD in creating a report on a disease not currently covered in this database may write to orphan@rarediseases.org.